1996 Commission report on the development, validation and legal acceptance of alternative methods to animal experiments in the field of cosmetics
Date: 1997-05-05
Institutions: European Commission
Subjects: OECD, animal experimentation, cosmetic product, product safety, report

COMMISSION OF THE EUROPEAN COMMUNITIES 

Brussels,  05.05.1997 
COM(97)  182  final 

1996 COMMISSION REPORT 
ON THE DEVELOPMENT, VALIDATION AND LEGAL 
ACCEPTANCE OF ALTERNATIVE METHODS TO ANIMAL 
EXPERIMENTS IN THE FIELD OF COSMETICS. 

SUMMARY 

PARTI 

TABLE OF CONTENTS 

1996 COMMISSION REPORT 

A. INTRODUCTION AND BACKGROUND 

B. OBJECTIVES AND CONSTRAINTS 

1. Consumer  safety 

2. The  reduction  and  elimination  of animal suffering 

3.  International  aspects and  the GATT/TBT rules 

4. The  interests  of the SMEs 

C. EXISTING AND EXPECTED RESULTS 

1. Tests on  ingredients  and  combinations  of ingredients 

2. Finished  cosmetic  products 

4 

8 

8 

9 

9 

10 

12 

14 

14 

14 

16 

D. CONCLUSIONS  DRAWN BY THE COMMISSION  FROM THESE 
OBJECTIVES, CONSTRAINTS AND RESULTS  IN ITS DRAFT  DIRECTIVE 
PARTIALLY  POSTPONING THE DEADLINE OF 1 JANUARY  1998 AND IN 
ITS REFLECTIONS  ON THE PRESENTATION  OF A PROPOSAL  FOR A 
EUROPEAN  PARLIAMENT AND COUNCIL DIRECTIVE AMENDING  ARTICLE 
17 
4(1)(l) OF THE BASIC DIRECTIVE 

E. CONCLUSIONS AND OUTLOOK 

18 

A 

PART 2 

SCIENTIFIC ASPECTS 

A. INITIATIVES TAKEN IN 1996 

1. ECVAM 

2. Scientific  Committee  on Cosmetology  (managed  by DG XXIV) 

3. DG XII 

4. COLIPA 

5. OECD... 

B. STATISTICS ON ANIMAL EXPERIMENTS 

C. STATE OF PROGRESS IN 1996 IN EACH INDIVIDUAL AREA 

1. Photoirritation/phototoxicity 

2. Percutaneous  absorption 

3.  Eye irritation 

4. Skin  irritation 

5. Skin  sensitisation 

6. Skin  compatibility  of the  finished  product 

21 

21 

21 

22 

22 

23 

24 

25 

26 

26 

27 

30 

30 

31 

32 

Summary 

INTRODUCTION AND BACKGROUND 

This  1996 report is the third report to be presented by the Commission.  It  reviews 
the  situation  at  October  1996, i.e. just  before  the  date  by  which  the  Commission 
had to present draft  measures postponing  the date for the ban on animal  testing  in 
cases  where  alternative  methods  of testing  have  not  been  scientifically  validated 
as offering  an equivalent level of protection  for the consumer, taking  into  account 
OECD  guidelines.  It  belongs  in the  context  of  the  sixth  amendment  to  the  basic 
Cosmetic  Products  Directive  adopted  by the  Council  on  14 June  1993  (Directive 
93/35/EEC), which provides  for  the  banning  of  cosmetic  products  which  contain 
ingredients or combinations  of ingredients tested on animals as of  1  January  1998 
unless  alternative  methods  are  not  available  by  this  date,  in  which  case  the 
Commission  must  present  draft  measures  to  postpone  the  ban.  The  sixth 
amendment  also  provides  that  the  Commission  shall  present  annual  progress 
reports to the EP and Council. 

The  1996 report consists of two parts. The first, more general part: 

- 

- 

- 

describes the objectives and constraints which have to be addressed. 

summarises the existing and expected results, 

specifies  the conclusions drawn by the Commission  from  these  objectives, 
constraints  and  results  in  preparing  its  draft  proposal  for  a  Directive 
postponing the deadline of  1  January  1998. 

The second part of the report is more scientific.  It explains: 

- 

- 

- 

the  initiatives  taken  in  1996  by  the  various  parties  involved  in  the 
research, validation and legal acceptance of alternative methods. 

the difficulties  involved in obtaining statistics, 

the state of progress in each individual  domain. 

OBJECTIVES AND  CONSTRAINTS 

There  are  two  key  objectives  -  namely  ensuring  the  safety  of  cosmetic  products 
for human health and the elimination/reduction of animal  suffering. 

Cosmetic  products,  which  include  personal  hygiene  products,  are  used 
throughout  a  person's  life.  The  Cosmetic  Products  Directive  makes  it 
incumbent  on manufacturers  to  ensure  that  cosmetic  products  are  safe  for 
human  health  and,  as  of  1  January  1997,  to  keep  a  safety  information 

dossier  which  will  be  accessible  to  the  monitoring  authorities.  The 
Cosmetic  Products  Directive  has  also  established  a  system  of  lists  of 
substances 
to  restrictions,  or  authorised 
respectively. These lists are regularly  adapted to technical  progress, on the 
the  Scientific  Committee  on 
basis  of  an  opinion  delivered  by 
Cosmetology, which takes into account the results of tests. 

that  are  banned,  subject 

The  banning  of  all  new  ingredients  would  not  make  tests  superfluous 
because the safety  of ingredients must be regularly  reexamined  in the light 
of  scientific  progress. Neither  can  one  outlaw  all  innovation  -  a  measure 
which would bankrupt numerous SMEs. 

- 

The reduction and elimination  of animal  suffering  is an ethical  imperative. 
Although  animal tests in the field  of cosmetic products account  for  a mere 
0.03% of all animal tests, they have been given priority. 

The report describes the work done in  1996 by the following  parties: 

* 

* 

* 

* 

the Commission and notably ECVAM, the European Centre for the 
Validation  of  Alternative  Methods,  a  unit  of  the  Joint  Research 
Centre; DG XI "Environment, Nuclear  Safety  and Civil  Protection, 
which manages Directive  86/609 on the protection  of animals used 
for  scientific  and  experimental  purposes;  DG XII  "Science, 
Research  and  Development",  in  funding  research  programmes; 
DG XXIV  "Consumer  Policy",  which  manages  the  Cosmetic 
Products Directive and the Scientific  Committee on  Cosmetology. 

the Scientific  Committee  on'Cosmetology; 

COLIPA/the  European  Cosmetic,  Toiletry 
Association; 

and  Perfumery 

the OECD. 

However,  the  report  emphasises  that  the  development,  validation  and  acceptance 
of alternative  methods  is a process  which  has  proven  more  complex  and  arduous 
than  initially  foreseen  and  that,  as  in  all  scientific  research,  it  is  impossible  to 
guarantee  a precise result by a given date. The report also  stresses that the  utmost 
prudence  is  called  for  as  regards  the  use  of  human  volunteers,  who  cannot  serve 
as a substitute  for animal experiments pure and simple. 

The constraints that have to be borne in mind are mainly: 

* 

compliance with the rules of international trade, notably those of the  WTO 
(World  Trade  Organisation).  The  point  is  that  any  measure  having  the 
effect  of  banning  products  from  third  countries  on  the  grounds  that  these 
products  have  been  tested  on  animals  poses  problems  of  compatibility 
with  the  rules  of  international  trade.  It  would  appear  necessary  to 
investigate  the  subject  in  greater  detail  in the  context  of  preparing  an  EP 

and  Council  Directive  which  the  Commission  intends  to  propose  during 
the  coming  months,  designed  to  amend  the  basic  Cosmetic  Products 
Directive  so as to address, in a legally  appropriate  text, the ban on  animal 
testing by regulating in particular the question of finished  products. 

the  interests  of  the  employment-generating  SMEs,  which  also  must  be 
taken into account.  Measures must be taken to ensure that they are trained 
and  informed. 

EXISTING AND EXPECTED  RESULTS 

The  results  are  summarised  in the first part  of the report  and  described  in  greater 
detail in the second part. 

A  distinction  must  be  made  between  (a)  ingredients  and  combinations  of 
ingredients and (b) finished  cosmetic products. 

As  regards  tests  on  ingredients/ combinations  of  ingredients  the  report  makes  it 
clear  that  no  alternative  method  offering  an  equivalent  degree  of  protection  is 
available to date, or likely to be available by  1  January  1998. 

Methods  which  do  not  involve  animal  trials  will  however  become  progressively 
available  in the  fields  of  percutaneous  absorption  and  local  risks  to  the  eye  and 
skin: photoirritation, eye irritation and skin irritation. 

However,  as  regards  tests  concerning  the  system  risks  -  i.e.  risks  involving 
exposure  of the organism  as a whole  as opposed  to  local  risks -  there  is no  hope 
that  animal  trials  can  be  replaced  on  schedule.  However,  the  number  of  animals 
used is being steadily reduced. 

In general  it will  be possible  to  evaluate  the  safety  of the finished  products  after 
1 January  1998  without  recourse  to  animal  trials,  thanks  notably  to  existing 
knowledge on the safety  of the ingredients, and  by methods not  involving  the  use 
of  animals,  even  if  these  methods  are  not  liable  to  be  the  subject  of  an  OECD 
ingredients  and  combinations  of 
guideline,  which  deals  exclusively  with 
ingredients. However, in certain cases there may be a risk of toxic effects,  due  for 
example to the interaction  of the ingredients or to the fact  that skin penetration  of 
the  ingredients  is  facilitated  by  the  vehicle  used.  In  such  cases  tests  on  animals 
would remain necessary. 

CONCLUSIONS  DRAWN  BY  THE  COMMISSION  FROM  THESE 
OBJECTIVES, CONSTRAINTS AND RESULTS 

The  Commission's  draft  directive  designed 
the  deadline  of 
1 January  1998 takes into account the objectives, constraints and results described 
in the report. 

to  postpone 

The  Commission  notes  that,  while  progress  has  been  made  in  research  into 
alternative test methods, notably in the fields of percutaneous absorption and local 
risks to the eyes and skin, the fact remains that no alternative method has yet been 
scientifically  validated  and  accepted  andthat  the  OECD  has  not  yet  adopted 
pertinent guidelines on toxicity tests in the field of alternative testing methods. 

The situation is unlikely to change before  1  January  1998. 

Hence  the  draft  Directive  proposes  the  postponement  of  the  date  mentioned  in 
Article  4(1 )(i) of  Directive 76/768/EEC,  in  compliance  with the  second  sentence 
of that provision, until  30 June 2000, before  which date it can be foreseen  that no 
alternative  testing  method  will  have  been  adequately  scientifically  validated  and 
accepted. 

It  also  provides  that  before  1  January  2000  the  Commission  shall  present  draft 
measures taking into account progress made by that date. 

The  Commission  also  wishes  to  promote  research  into  and  the  validation  of 
alternative methods. 

As regards finished products, the Commission  will take measures to  promote  the 
dissemination  among SMEs of methods not involving the use of animals. 

The Commission has also initiated reflections  and intends, in the coming months, 
to  present  a  proposal  for  a  European  Parliament  and  Council  Directive  on  the 
amendment of Article 4 (1) (i) to address, in a legally appropriate text, the ban on 
animal testing in respect of finished  cosmetic products -  barring exceptional  cases 
-  as  of  1  January  1998,  in  order  to  comply  with  the  requirements  of  Directive 
76/768. 

This  proposal  for  a  Directive  should  also  regulate  aspects  relating  to  products 
from  third  countries  and  clarify  certain  concepts  and  references  in  the  text  that 
have given rise to questions. 

Since  the  Directive  will  be  based  on  Article  100a,  this  Commission  proposal 
requires the approval of the European Parliament and the Council. 

f 

P A R T! 

1996 Commission Report 

on the development, validation and legal acceptance of alternative methods to animal 
experiments in the field of cosmetics. 

A. 

INTRODUCTION AND BACKGROUND 

The Commission has already presented two annual reports on  1994 and  1995 data 
concerning  progress  in  the  development,  validation  and  legal  acceptance  of 
alternative methods to animal experiments in the field of cosmetics. 

This  1996 report reviews the scientific  situation at October  1996. 

This  1996  report  belongs  in  the  context  of  Directive  76/768/EEC  on  cosmetic 
products,  whose  new Article  4 (1)  (i), introduced  by  Council  Directive  93/35  of 
14 June  1993, provides that Member States shall ban the placing on the market of 
cosmetic products containing ingredients or combinations of ingredients tested on 
animals after  1  January  1998 in order to meet the requirements of this Directive. 

However,  this  Article  specifies  that  "if  there  has  been  insufficient  progress  in 
developing  satisfactory  methods  to  replace  animal  testing,  and  in  particular  in 
those  cases  where  alternative  methods  of  testing,  despite  all  reasonable 
endeavours, have not  been  scientifically  validated  as offering  an equivalent  level 
of protection for the consumer, taking into account OECD toxicity test guidelines, 
the  Commission,  shall, by  1  January  1997, submit draft  measures to postpone  the 
date  of  implementation  of this  provision,  for  a  sufficient  period,  and  in  any  case 
for  no  less than two years, in accordance with the procedure  laid down  in Article 
10. Before  submitting  such measures, the Commission  will  consult the  Scientific 
Committee on Cosmetology". 

This  1996 report  comprises  two parts. The first, more  general  part,  describes  the 
objectives  and  constraints  that  have  to  be  addressed,  the  existing  and  expected 
results  as  regards  ingredients  and  combinations  of  ingredients  on  the  one  hand 
and finished products on the other, and the conclusions drawn by the  Commission 
from  these objectives,  constraints  and results  in preparing  its draft  proposal  for  a 
Directive to postpone the deadline of  1  January  1998. 

The second part of the report is more scientific. It describes: 

the  initiatives  taken  in  1996  by  the  different  parties  involved  in  the 
development,  validation  and  legal  acceptance  of  alternative  methods, 
specifying  wherever possible the cost of these initiatives 

- 

the difficulties  in obtaining statistics 

8 

the state of progress in each individual  domain. 

B. 

OBJECTIVES AND CONSTRAINTS 

Two principal objectives  must be pursued and wherever possible reconciled  in the 
field  of  cosmetic  products:  (a)  ensuring  consumer  safety  and  (b)  reducing  and, 
ideally, eliminating animal  suffering. 

Moreover, various constraints must be borne in mind, the two primary  ones  being 
(a) the  international  arena  and the  need  to  comply  with  WTO rules  and  the  rules 
of free  competition, and (b) the interests of firms, notably  employment-generating 
small and medium-sized  enterprises. 

1. 

Consumer safety 

Consumer  safety  must remain paramount.  Here it should  be noted  that  the 
notion  of  "cosmetic  products"  encompasses  not  only 
so-called 
"decorative"  products,  such  as  lipstick  or  nail  varnish,  but  also  articles 
such  as  soap,  shampoos, toothpaste  which  are used  throughout  a  person's 
lifetime  from  early childhood on. It is essential  that these products  should 
not  cause  harmful,  immediate  and  visible  effects,  such  as  irritation,  or 
long-term,  latent  effects  such  as risks  of carcinogenicity  or  teratogenicity, 
etc. 

To  ensure  that  cosmetic  products  are  safe  for  human  health  in  all  these 
respects, it is necessary to check not only the safety  of the finished  product 
but  also -  and primarily  -  that  of the  ingredients  used  in  its  manufacture. 
It  is  for  the  manufacturer  to  ensure  the  safety  of  the  ingredients,  in 
compliance  with  Article  2  of the  Cosmetic  Products  Directive,  according 
to  which  cosmetic  products  must  not  be  liable to  cause  damage  to  human 
health  when 
they  are  applied  under  normal  conditions  of  use; 
manufacturers  may also be held liable  in the event of damages pursuant  to 
liability  for  defective  products. 
Council  Directive  85/374/EEC  on 
Pursuant  to  Council  Directive  93/35/EEC  of  14 June  1993  amending  for 
the  sixth  time  the  basic  Cosmetic  Products  Directive,  the  manufacturer 
must,  as of  1  January  1995, keep  certain  information  readily  accessible  to 
the  competent  authorities,  including  "assessment  of  the  safety  for  human 
health of the finished  product. To that end the manufacturer  shall take  into 
consideration  the ' general  toxicological  profile  of  the  ingredient,  its 
chemical structure and its level of exposure." 

The  Cosmetic  Products  Directive  also  includes  a  series  of  annexes 
featuring  positive and negative lists of substances. The general principle  is 
that  substances  may be used  freely,  unless they  are prohibited  (Annex  II), 
or subject to certain limitations and conditions (Annex III). There are three 
the  only  colouring  agents, 
exceptions 
preservatives and UV filters authorised  are those featuring  in positive  lists 
(Annexes IV, VI and VII). 

this  general  principle: 

to 

A  substance  can  only  be  included  in  these  lists,  which  are  adapted  to 
technical progress each year by a Commission  Directive, if it has been  the 
subject  of  an  opinion  delivered  by 
the  Scientific  Committee  on 
Cosmetology  concerning  its toxicity  for  human  health.  This  SCC  opinion 
is prepared  on the  basis  of  all  the  existing  scientific  data  and  notably  the 
test  results  furnished  by  industry,  which  may  concern  sensitisation, 
mutagenicity, 
photoirritation, 
carcinogenicity, teratogenicity, and acute, subchronic  and chronic  toxicity, 
etc. 

irritation, 

irritation, 

skin 

eye 

While  some  7 000  substances  are  already  used  in  cosmetic  products  and 
while  for  many  cosmetic  substances  new tests  are  not  generally  required. 
it should  however be stressed  that  such tests  may  sometimes  be crucial  in 
reevaluating,  on  the  basis  of  technical  progress  and  new  scientific 
knowledge,  certain  substances  which  have  been  in  use  for  a  very  long 
time.  Hence  each  year  the  SCC  examines  a  series  of  banned  substances 
(numbering  approximately  400)  and  substances  subject 
to  certain 
limitations and requirements (numbering  approximately  50). 

It  must  also  be  possible  to  examine  the  risks  associated  with  the  use  of 
these products in combination. Thus on safety  grounds it is not possible to 
dispense  entirely  with  animal  trials, even  in respect  of  substances  already 
in  use.  Moreover,  in  the  cosmetic  products  sector  -  as  in  all  other 
industrial  sectors  -  it  would  be  neither  wise  nor  reasonable  to  bring 
innovation  to  a standstill.  Even  if  consumers  were  to  foresake  their  quite 
legitimate  hope  of  obtaining  ever  better  products,  a  blanket  ban  on 
innovation  by  outlawing  the  use  of  new  substances  would  certainly  spell 
ruin  for  numerous  European  cosmetic  product  manufacturers,  mainly 
employment-generating  SMEs. 

The reduction  and elimination of animal  suffering 

Reduction  and,  where  possible,  elimination  of  animal  suffering  is  an 
objective  that  deserves  the  closest  attention  and  in  respect  of  which 
resources should be mobilised at all levels. 

This  objective  reflects  ethical  imperatives  concerning  respect  for  life, 
deep-seated public aspirations, and the wishes of the European  Parliament. 
It  finds  expression  in  several  European  instruments,  including  Directive 
86/609/EEC  on the protection  of  animals  used  for  experimental  and  other 
scientific  purposes  and  Directive  93/35/EEC  (the  sixth  amendment  to  the 
initial Cosmetic Products Directive). 

While  consumer  safety  must  be  assured,  we  must  also  do  our  utmost  to 
ensure  that  animal  tests  are  replaced  by  alternative  tests  as  soon  as 
possible, provided these afford  an equivalent  level of protection.  Although 
animal trials in the cosmetics field account  for  a mere 0.03% of all  animal 
tests  and  although  all  chemical  substances  already  have  to  be  tested  in 

10 

order  to  provide  the  toxicity  data  required  under  Directive  92/32/EEC, 
cosmetic  products  have  been prioritised  and  there  has  been  a major  drive 
in  recent  years,  notably  since  the  adoption  of  Directive  93/35/EEC,  to 
promote  the  development  of  alternative  methods.  These  endeavours,  as 
well as progress to date and the outlook for the future,  are described  in the 
1994  and  1995  annual  reports  on  the  development,  validation  and  legal 
acceptance  of  alternative  methods  to  animal  experiments  in  the  field  of 
cosmetic products, already presented by the Commission to the EP and the 
Council. 

Notably, these reports describe the work done by a number of players. Part 
II reviews the activities of these players in  1996. 

In particular, these players are: 

ECVAM (the European Centre for the Validation  of Alternative  Methods), 
a unit of the Ispra Joint Research  Centre, which coordinates the  validation 
of  alternative  methods  at  Community  level,  provides  a forum  for  pooling 
information  and works on the development,  updating  and  management  of 
a database and promotes dialogue between all interested parties. 

In  1996  ECVAM  continued  to  organise  workshops  of  direct  relevance  to 
evaluating  the  safety  of  cosmetic  products  (based  on e.g.  data  concerning 
alternative methods); it published  in ATLA recommendations  methods  for 
assessing  percutaneous  absorption  and  for  skin  sensitisation  testing,  and 
recommendations  on  the  application  of  biostatistical  methods  to  the 
development  and  validation  of  alternative  toxicological  methods;  it 
subsidised  and  coordinated  a study  for  testing  UV  filters  listed  in  Annex 
VII  to  the  Cosmetic  Products  Directive  (photoirritation);  it  conducted  a 
formal  validation  study  on  four  tests  of  skin  corrosion,  and  maintained 
regular  contacts  with  the  OECD  and  began  a  number  of  prevalidation 
studies relevant to the cosmetics industry. 

The  Commission  (DG  XI  "Environment,  Nuclear  Safety  and  Civil 
Protection")  which  manages  Directive  86/609/EEC  on  the  protection  of 
animals  used  for  experimental  or  other  scientific  purposes,  has  continued 
to  follow  the  matter.  The  Commission  (DG XII  "Science,  Research  and 
Development")  has  also  subsidised  research  programmes  including  the 
development of alternative methods. 

In  the  context  of  its  consumer  policy,  the  Commission  (DG XXIV)  has 
funded  research  and  participated  in  or  organised  meetings  with  all  the 
partners involved and organised and followed  up the meetings of the SCC. 

The Scientific  Committee  on  Cosmetology  -  whose  mandate  is to  deliver 
scientific  opinions to the Commission on ingredients  listed  in the Annexes 
to  the  Cosmetic  Products  Directive  and  on the  applicability  of  alternative 
methods  validated  in  the  process  of  evaluating  the  safety  of  cosmetic 
products, and on the proposal  for  a Directive  which  the Commission  must 

il 

present concerning the postponement of the deadline for the ban on animal 
tests  in  cases  in  which  alternative  methods  will  not  be  available  by 
1 January  1998 -  met on numerous  occasions  in  1996 both  in plenary  and 
in  its  Alternative  Methods  Subcommittee,  sometimes  jointly  with  the 
European  Industry.  Besides  the  activities  documented  in  Part  II, the  SCC 
adopted  in  1996  a  document  titled  "The  use  of  alternatives  to  animal 
studies in the safety  evaluation of cosmetic  ingredients  or combinations  of 
ingredients". 

Finally,  at  OECD  level,  work  has  been  done  on  percutaneous  absorption 
(meeting of the national coordinators in Paris in September  1996). 

It is important  to note that the development,  validation  and  acceptance  of 
alternative  methods  cannot  be  achieved  overnight,  despite  all  the  effort 
that is being  invested. 

Hence  the  validation  phases  -  i.e.  the  complex  process  by  which  the 
pertinence,  reliability  and  reproducibility  of  a  test  developed  for  routine 
application  and legal acceptance  is evaluated  and monitored  -  have turned 
out  to  be  more  numerous  and  complex  than  initially  foreseen,  and  new 
phases have had to be  incorporated. 

Moreover,  as  in  the  case  of  all  scientific  research,  it  is  well-nigh 
impossible  to  guarantee  a  precise  result  by  a  given  date,  and  certain 
studies, which were thought to be on the verge of completion -  such as the 
EU/HO  study  on  alternatives  to  the  Draize  test  -  turned  out  to  be 
disappointing  as regards the predictability  of the risk. 

As regards  alternative  tests  on human  volunteers,  for  example  in the  field 
of skin  irritation, the utmost prudence  is called  for;  such tests  should  only 
be countenanced  in the proven absence of real risks. 

For  all that, progress  to  date  has  already  made  it  possible  to  substantially 
reduce  the  number  of  animals  used  and  to  mitigate  their  suffering.  -  for 
example  the  use  of  three  basic  in  vitro  mutagenicity  tests  will  obviously 
lead to further  improvements  in the  future. 

3. 

International  aspects and the GATT/TBT rules 

It  is  important  to  note  that  any  measure  that  leads  to  banning  the 
importation of cosmetic products into the Community  solely because these 
products  or  their  ingredients  have  been  tested  on  animals  might  prove 
incompatible, with the rules of international trade. The main restriction that 
public  international  law  imposes  on  a  state  is  to  forbid  -  except  in  the 
event  of  a  specific  rule  to  the  contrary  - any  exercise  of  its  power  on  the 
territory  of another state. 

12 

Firstly,  the  WTO  outlaws  quantitative  restrictions  on  imports  (Art  XI§1). 
Moreover,  Article  III §4  proscribes  all  discriminatory  measures  between 
like products,  i.e.  in accordance  with  the  accepted  interpretation,  products 
which  do  not  present  physical  differences.  Since  the  test  method  clearly 
has  no  physical  effect  on  the  product,  a  discrimination  based  on  this 
criterion might be held to fall  foul  of Article III§4. 

Finally,  such  a measure  would  not  be  easy  to justify  in the  context  of  the 
general  exceptions  featured  in  Article  XX  of  the  GATT  (and  more 
specifically  subsection  b), which  authorises  -  within  the  terms  of  Article 
XX  -  measures  "necessary  to  protect  human,  animal  or  plant  life  or 
health".  In the  absence  of case  law  in this  area,  it  is not  possible  to  claim 
that protection of animal welfare  could be covered by the exception. 

Secondly,  as  regards  measures  designed  to  verify  compliance  with  the 
provisions  of  the  Cosmetic  Products  Directive  -  viz.  requirements  in 
regard to the protection of human health -  the provisions of the Agreement 
on Technical  Barriers  to Trade  (TBT)  and notably  those  of Article  6 must 
be borne in mind. Article 6 promotes the mutual recognition  of  conformity 
evaluation  procedures:  "Members  shall  ensure  that,  whenever  possible, 
that  results  of  conformity  assessment  procedures  in  other  Members  are 
accepted, even when these procedures differ from  their own, provided  they 
are  satisfied  that  those  procedures  offer  an  assurance  of  conformity  with 
applicable  technical  regulations  or  standards  equivalent  to  their  own 
procedures". 

Bearing  these  provisions  in  mind,  the  extraterritorial  application  of  a 
Community measure banning animal'trials  could be considered as contrary 
to the  Community's  international  commitments.  Moreover,  Article  4(1 )(i) 
of  this  Directive  specifies  that  the  ban  on  animal  testings  may  be 
postponed  if  there  are  no  scientifically  validated  alternative  methods 
which  offer  the  consumer  an  equivalent  degree  of  protection.  Hence  it 
would  be  difficult  to  deny  the  equivalence,  from  the  viewpoint  of  human 
health  protection,  of  animal  tests  with  alternative  test  methods  which  are 
recognised  as equivalent. 

It should be noted  that the rationale  behind the ban  is not that  animal  tests 
do not permit  correct  assessment  of compliance  with the provisions  of the 
is  based  purely  on  ethical 
Cosmetic  Products  Directive,  but 
considerations. 

Thus  any  decision  on  the  use  of  alternative  methods  could  also  be 
challenged  if  it  were  adopted  on  a  unilateral  basis.  Moreover  the  TBT 
Agreement  strongly  encourages  the  members  of  the  WTO  to  adopt  the 
pertinent  international  systems  for  assessment  of  the  conformity  of  a 
technical  regulation  (Article  9). However,  Article  9 also  specifies  that  this 
applies  only  to  the  extent  that  these  international  systems  are  in 
compliance  with  the  provisions  of  Articles  5 and  6 of  the  selfsame  TBT 
Agreement  (Article 9§3). 

Thus  it  is  very  important  to  remain  at  least  within  the  framework  of  the 
Organisation  for  Economic  Cooperation  and  Development  (OECD),  to 
which moreover Directive 93/35 refers. 

Part  II  of  this  report  explains  the  role  played  by  the  OECD  in  regard  to 
alternative  methods  in  the  different  domains  of  the  safety  of  cosmetic 
products  and  highlights  the  close  links  which  the  Commission  has  also 
developed and maintains with the OECD in this specific  field. 

The  Commission  is  reflecting  on  to  all  matters  relating  to  the  rules  of 
international  trade  in  the  context  of  preparing  a proposal  for  a  European 
Parliament  and  Council  Directive  designed  to  amend  the  basic  Cosmetic 
Products  Directive  to  address,  in  a  legally  appropriate  text,  the  ban  on 
animal  testing,  notably  by  regulating  the  question  of  finished  cosmetic 
products. 

4. 

The interests of the SMEs 

the  reasonable 

imperative  to 
Finally,  apart  from  consumer  safety  and  the  ethical 
reduce/eliminate  animal  suffering, 
the 
cosmetics  industry  should  also  be taken  into  consideration,  notably  those 
of  the  employment-generating  SMEs.  The  alternative  methods  to  be 
developed  should be accessible to SMEs, even if they do not have as many 
"in-house" toxicologists or the same amount of experience or field data, or 
the  internal  laboratories  and  financial  resources  available  to  the  large 
firms. 

interests  of 

In  this  context,  COLIPA  will  be  launching  a  major  drive  to  provide 
information  and  training,  in  collaboration  with  its  large  member  firms. 
Moreover,  it  seems  that  specialised  laboratories  are  springing  up  whose 
services  the  SMEs  will  be  able  to  draw  on  for  alternative  trials,  as  and 
when such trials reach maturity. 

ECVAM could also be involved -  possibly together with  COLIPA  (Scaat) 
-  in  training  SMEs  in  the  use  of  alternative  methods  for  evaluating  the 
safety  of cosmetic products. 

C. 

EXISTING  AND EXPECTED RESULTS 

1. 

Tests on ingredients and combinations  of ingredients 

It should be noted that, as shown in Part  II, no alternative method  offering 
consumers  an  equivalent  degree  of  protection  has  yet  been  scientifically 
validated  and  accepted  by  the  regulatory  authorities.  The  OECD  has  not 
yet adopted pertinent guidelines for toxicity tests in the field of alternative 
testing  methods  for  ingredients  and  combinations  of  ingredients  used  in 
cosmetic products. 

14 

However  progress  has  been  made  and  it  looks  as  though  alternative 
methods  will  progressively  become  available  in  the  various  safety 
domains  pertaining  to  percutaneous  absorption  and  local  risks  to  the  eye 
and skin (photoirritation, eye irritation and skin irritation). 

However,  these methods  will  not  be  validated  and accepted  by  1 January 
1998,  despite  the  high  expectations  that  were  had,  mainly  in  regard  to 
percutaneous absorption and photoirritation. 

In  regard  to  percutaneous  absorption  and  local  risks,  the  situation  is  as 
follows: 

Photoirritation 

Photoirritation  mainly  concerns  UV  filters.  A  special  study  to  follow  the 
EU/COLIPA  validation  study  is  scheduled  for  1996.  This  is  directed  by 
Zebet,  and  subsidised  and  coordinated  by  ECVAM.  The  study  should 
make it possible to test UV filters in Annex  VII to the Cosmetic  Products 
Directive  and  to  prepare  a  protocol  with  a  view  to  submitting  a  draft 
guideline  to  the  OECD.  The  first  results  of  this  special  study  should  be 
available by September  1997. 

Percutaneous absorption 

In  May  1996,  after  discussions  with  the  Commission,  the  industry 
presented  the  OECD  with  a draft  new  guideline  on  in  vitro  percutaneous 
absorption.  "In-house"  data  were  provided  to  support  this  dossier.  A 
meeting  of  the  OECD  national  coordinators'  group  was  held  in  Paris  in 
September  1996, but the rate of progress toward acceptance slow. 

The  Scientific  Committee  on  Cosmetology  has  emphasised  that  the  test 
protocols  used  by  industry  had  not  yet  been  subjected  to  the  formal 
validation study and that the documentation was incomplete. However, the 
SCC  has  in  recent  years  agreed  to  use  in  vitro  percutaneous  absorption 
data in evaluating the safety  of several cosmetic ingredients. 

Eye irritation 

The  1995  Report  stressed  that  the  results  of  the  validation  studies  of 
alternative  methods to the Draize eye irritancy test had been  disappointing 
(EU/Home Office  study and COLIPA study). 

ECVAM  and  COLIPA  held  a  meeting  in  December  1996  to  discuss  the 
outcomes of the EC/HO and COLIPA studies and plan new initiatives. 

15 

Skin irritation 

ECVAM  has  conducted  a  formal  validation  study  involving  four  skin 
corrosion tests, whose results are expected in  1997. 

The  OECD  is  also  planning  a draft  testing  strategy  to  determine  the  skin 
irritation potential of chemical substances. 

The draft  OECD  strategy  is to use  a hierarchical  approach  by  eliminating 
severe  skin  irritants  through  consideration  of  the  structure  activity 
relations  (SAR's)  and  structure  property  relations  (SPR's)  and  data 
obtained  from  in  vitro  corrosion  tests,  before  considering  the  use  of 
conventional  in vivo tests on rabbits or the use of human volunteers. 

A  summary  of  the  situation  regarding  local  risks  shows  that  progress 
should  proceed  apace  but  that  1  January  1998  is  too  early  for  the 
replacement  of animal  trials. However,  as regards reducing  the number  of 
animals  and  their  suffering,  it  may  be  noted  that  in practice  in  vitro  tests 
are already  used  as screening  or  guideline  tests  and that  certain  data  have 
already been provided to the SCC. 

Skin sensitisation 

Research has led to a better understanding  of the scientific  bases of 
skin sensitisation. 

ECVAM  is to take action  in the light of the report  of the  ECVAM 
workshop on this topic. 

Mutagenicity 

The  combination  of  three  basic  in  vitro  tests  already  makes  it 
possible to demonstrate a mutagenic potential and this combination 
is  already  being  applied  in  evaluating  the  safety  of  cosmetic 
ingredients. 

All tests on ingredients relating to systemic effects 

toxicity,  subchronic 

(Acute 
toxicity,  carcinogenicity, 
teratogenicity).  Because  they  are  linked  to  exposure  of  the 
organism  as  a  whole,  there  is  no  hope  that  alternative 
methods  to  replace  animal  trials  will  be  available  in  the 
foreseeable  future. 

However,  the  refinement  of  the  methods  used  has  already 
made it possible to reduce the number  of animals  used  and 
mitigate their suffering,  and this trend is likely to continue. 

2. 

Finished cosmetic products 

16 

As  regards  finished  cosmetic  products,  progress  to  date  suggests  that  it 
will  generally  be possible to evaluate their safety  on the basis of available 
knowledge  on the  toxicity  of  their  ingredients  and  their  physicochemical 
properties, using methods which do not involve the use of animals, even if 
these methods are not liable to be the subject of an OECD guideline which 
deals dealing only with ingredients and combinations of ingredients. 

Hence  it  will  only  be  necessary  to  resort  to  animal  testing  in  rare, 
exceptional  cases, where there are grounds to fear that the toxic effects  of 
the  ingredients  may  be potentiated,  notably  when  skin  penetration  of  the 
ingredients  is  facilitated  by  the  vehicle  used  or  when  such  effects  result 
from  the interaction  of the ingredients. The  SCC has emphasised  this  fact 
in its Guidelines on the use of alternative methods to animal  studies in the 
safety  evaluation of cosmetic ingredients or combinations of ingredients of 
24 Mav  1996. 

Certain  cosmetics  firms  already  very  often  use  methods  which  do  not 
involve the use of animals to test their finished  products. 

COLIPA  (the  European  Cosmetic,  Toiletry  and  Perfumery  Association) 
has  announced  that  it  could  progressively  establish  a  voluntary  ban  on 
animal  testing  for  finished  cosmetic  products  -  except  in  the  exceptional 
cases  referred  to  above -  for  the  entire  European  cosmetics  industry,  and 
that  it  would  be  willing  to  organise  technology  transfer  in  this  respect. 
COLIPA  has  also  said  that 
the  widest  possible 
dissemination  of  findings  in  this  area  and  promote  training  in  European 
companies  and  laboratories;  this  training  could  be  coordinated  by  the 
Commission's  services.  The  Commission,  in  particular,  will  promote  the 
dissemination  of  methods  not  involving  animals  among  the  SMEs.  It 
could also endeavour to promote such measures at international  level. 

it  could  ensure 

D. 

CONCLUSIONS  DRAWN  BY  THE  COMMISSION  FROM  THESE  OBJECTIVES, 
CONSTRAINTS  AND  RESULTS  IN  ITS  DRAFT  DIRECTIVE  PARTIALLY  POSTPONING 
THE  DEADLINE  OF  1 JANUARY  1998  AND 
ITS  REFLECTIONS  ON  THE 
PRESENTATION  OF  A  PROPOSAL  FOR  A  EUROPEAN  PARLIAMENT  AND  COUNCIL 
DIRECTIVE  AMENDING ARTICLE 4(1)(I)  OF THE BASIC DIRECTIVE 

IN 

1. 
The draft  Directive prepared by the Commission takes account  of the  fact 
that,  while  progress  has  been  made  in  research  into  alternative  test  methods, 
notably  in  the  fields  of  percutaneous  absorption  and  local  risks  to  the  eyes  and 
skin,  the  fact  remains  that  no  alternative  method  has  yet  been  scientifically 
validated  and  accepted.  The  OECD  has  not  yet  adopted  pertinent  guidelines  for 
toxicity tests in the field of alternative testing methods. 

The situation is unlikely to change before  1  January  1998. 

17 

Hence  the  draft  Directive  proposes  the  postponement  of  the  date  mentioned  in 
Article  4(1 )(i)  of Directive 76/768/EEC,  in compliance  with  the  second  sentence 
of that provision, for not less than two years. 

Currently  it  is  difficult  to  predict  precisely  when  certain  alternative  methods  for 
testing  certain  ingredients  or  combination  of  ingredients  will  be  scientifically 
validated.  However  as  it  is  likely  that  alternative  methods  will  progressively 
become  available  in  the  field  of  percutaneous  absorption,  photoirritation,  eye 
irritation  skin  irritation  and  skin  sensitivation,  and  whereas,  besides,  the 
Commission  is  mindful  of  the  objective  of  Article  4(1 )(i),  the  draft  Directive 
postpones the deadline to a date by which it can be foreseen  no alternative  method 
will have been adequately scientifically  validated and accepted, viz. 30 June 2000. 
It  also  stipulates  that  before  1  January  2000  the  Commission  shall  present  draft 
measures taking into account progress made by that date. 

Finally,  in  the  context  described  above,  and  also  in  compliance  with  the 
provisions  of  Article  130f(3)  of  the  Treaty  and  Fourth  Research  Framework 
Programme,  the  Commission  will  take  the  necessary  measures  to  promote 
research  into  and  the  validation  of  alternative  methods  to  animal  testing  in  the 
field  of  ingredients  and  combinations  of  ingredients 
in  cosmetic  product 
formulations.  This  could  take  the  form  of  a  recital  in  the  draft  proposal  for  a 
Directive. 

Presentation  of  a  proposal  for  a  European  Parliament  and  Council 

2. 
Directive amending Article 4(1 )(i) of the basic Directive 

In the  context  described  in point  C.2. above relating  to the  existing  and  expected 
results  for  finished  cosmetic  products,  the  Commission  has  initiated  reflections 
and  intends,  in  the  coming  months,  to  present  a  proposal  for  a  European 
Parliament and Council Directive amending Article 4 (1) (i) in order to address, in 
a legally appropriate text, the ban on animal testing in regard to finished cosmetic 
products  -  barring  exceptional  cases  -  as  of  1.1.1998,  in  order  to  respect  the 
obligations of Directive 76/768. 

This  proposal  for  a  Directive  should  also  regulate,  in  a  legally  appropriate  text, 
aspects  concerning  products  from  third  countries,  and  clarify  the  concept  of 
"finished  products". 

Since  the  Directive  will  be  based  on  Article  100a,  this  Commission  proposal 
requires the approval of the Council and the European Parliament. 

E. 

CONCLUSIONS  AND OUTLOOK 

1. 

This  report  reviews  the  situation  in  the  immediate  run-up  to  the  date  by 
which  the  Commission  must  present  a  draft  measure  postponing  the 
deadline  of  1  January  1998  in  areas  in  which  alternative  methods  for 
testing  ingredients  and  combinations  of  ingredients  will  not  be  available 
by that date. 

2. 

Two objectives  must be pursued: consumer safety,  which the  Commission 
the 
compromised 
insists  must 
elimination/reduction of animal  suffering. 

any  way, 

and 

not 

be 

in 

* 

* 

Banning all new ingredients would not remove the need for  animal 
tests because the  safety  of ingredients  has to be reexamined  in the 
light  of  new  scientific  knowledge.  Moreover,  blocking  all 
innovation  could  put  firms  out  of  business  and  in  particular  the 
that 
employment-generating  SMEs.  It  should  be  noted  also 
cosmetic products  include personal  hygiene products, products  for 
babies (...) and not only so-called  "decorative" products. 

Priority should be given to eliminating animal suffering  in the field 
of  cosmetic  products,  even  if  tests  in  this  domain  account  for  a 
mere  0.03% of  all  tests. The  Commission  (ECVAM,  DG XI,  XII, 
XXIV), the  Scientific  Committee  on Cosmetology,  the  OECD  and 
Industry continued to work to this end in 1996. 

However the validation process has turned out to be more complex than  foreseen. 
In  the  SCC's  opinion  the  utmost  prudence  is  called  for  as  regards  the  use  of 
human volunteers, who cannot simply serve as a stand-in for animal experiments. 

j. 

Two constraints must also be borne in mind: 

a) 

compliance  with  the  rules  of  international  trade,  notably  those  of  the 
WTO(World  Trade  Organisation).  The  point  is  that  any  measure  having 
the  effect  of  banning  products  from  third  countries  on  the  grounds  that 
these  products  have  been 
tested  on  animals  poses  problems  of 
compatibility  with  the  rules  of  international  trade.  It  would  appear 
necessary  to  investigate  the  subject  in  greater  detail  in  the  context  of 
preparing  an EP  and  Council  Directive  which the  Commission  intends  to 
propose during the coming months, designed to amend the basic  Cosmetic 
Products  Directive  so  as to  address,  in  a legally  appropriate  text,  the  ban 
on  animal  testing  by  regulating  in  particular  the  question  of  finished 
products. 

b) 

the interests of the SMEs, which must be trained and  informed. 

k 

As  regards  the  existing  and  expected  results,  a  distinction  must  be  made 
between ingredients/ combinations of ingredients and finished products. 

a) 

As  regards  ingredients  and  combinations  of  ingredients,  no 
alternative  method  will  be  ready  by  1  January  1998.  However, 
methods  should  progressively  become  available  for  percutaneous 
absorption,  photoirritation,  eye  irritation  skin  irritation  and  skin 
sensitivation. 

19 

However, in the case of tests concerning system risks, i.e. exposure 
of  the  entire  organism,  there  is  no  hope  for  alternative  methods 
maturing in the foreseeable  future. 

b) 

In  general,  it  should  be  possible  to  ensure  the  safety  of  finished 
products,  thanks  mainly  to  our  knowledge  of  the  ingredients, 
without resorting to animal testing, after  1  January  1998. However, 
the SCC has emphasised the need for exemptions to this rule in the 
case  of  toxic  effects  caused,  for  example,  by  interactions  of  the 
ingredients. 

c) 

Progress  has  however  already  made  it  possible  to  reduce  the 
number of animals used. 

5. 

The Commission  has drawn conclusions from  these objectives,  constraints 
and expected results: 

- 

the Commission has prepared  a draft  Directive postponing  the date 
of  1  January  1998  in  regard  to  ingredients  and  combinations  of 
ingredients. 

The Commission has also decided to pursue its deliberations on presenting 
a  proposal  for  a  European  Parliament  and  Council  Directive  amending 
Article  4  (1)  (i)  of  the  basic  Directive  in  order  to  address  the  ban  on 
animal testing, notably by regulating the question of finished products. 

20 

PART 2 

SCIENTIFIC  ASPECTS 

A. 

INITIATIVES TAKEN IN  1996 

1. 

ECVAM 

Of  the  workshops  organised  and/or  published  by  ECVAM  in  1995  and 
1996 on the development and validation of alternative tests, those of direct 
interest to the assessment of consumer safety  are as follows: 

Methods  for  Assessing  Percutaneous 
Absorption 
Angera, Italy; 30 May-3 June  1994 
Howes  et  al.  (1996)  ATLA  24,  81-
106 

Acute  toxicity  testing  in  vitro  and 
the  classification  and  labelling  of 
chemicals 
Angera, Italy;  18-22 April  1994 
Seibert  et  al.  (1996)  ATLA  24, 499-
510 

skin 

for 

Alternative  methods 
sensitisation testing 
Angera, Italy; 24-28 April  1995 
de Silva et al. (1996) ATLA 24, 683-
705 

The  development  and  validation  of 
expert systems for predicting  toxicity 
Angera, Italy;  1-4 October  1996 
Dearden  et  al.  (1997)  ATLA  24,  in 
press 

Current Status and Future 
Development of Databases on 
Alternative  Methods 
Neublberg, 
September 
preparation. 

Germany; 
1996.  Report 

12-15 
in 

Workshop  13. 

Workshop 16 

Workshop 19 

Workshop 24 

Workshop 25 

21 

ECVAM has also published in ATLA recommendations  on the application 
of  biostatistical  methods  in the  development  and  validation  of  alternative 
toxicological methods (ATLA 24, 511-530, 1996). 

Of the other ECVAM Task  Forces, those  dealing  with  Prevalidation,  Skin 
Irritation  and  Integrated  Testing  are  also  particularly  relevant  to  the 
cosmetic testing issue. 

In  addition  to  the  ECVAM  validation  studies  on  skin  corrosivitv  and 
phototoxicity,  prevalidation  studies were  begun  on modified  protocols  for 
the  bovine  corneal  capacity  and  permeability  (BCOP)  test  and  the 
fluorescein  leakage (FL) test. 

2. 

Scientific  Committee on Cosmetology  (managed  by DG XXIV) 

joint  meetings  with  COLIPA/SCAAT 

The Alternative  Methods/Guidelines  Subcommittee  of the  SCC  organised 
(15 February  1996, 
three 
19 March  1996,  24 April  1996),  a  meeting  with  the  Director  of  ECVAM 
(6 March  1996) and a meeting  designed  to draw conclusions  and  adopt  an 
opinion (6 May  1996), following  consultations with DG XXIV. 

During these meetings the following  points were addressed: 

a) 

b) 

c) 

d) 

e) 

Preparation  of  a  discussion  document  on  the  "use  of  alternative 
methods  to  animal  studies  in  the  safety  evaluation  of  cosmetic 
ingredients or combinations of ingredients. 

Examination  of  the  final  report  on  the  EC/HO  study  on  the 
validation of the Draize eye irritancy test. 

Examination  of  the  statistical  assessment  data  of  phase  1 of  the 
COLIPA study -  validation of the eye irritancy test in the rabbit. 

Discussion  with ECVAM's Unit head on the implementation  of the 
provisions  of  Article  4  of  Directive  93/35/EEC.  involving  a 
general review of the validation studies. 

Discussions  with  COLIPA/SCAAT  on  Industry's  approach  to  the 
implementation  of  Directive  93/35/EEC,  which  is  based  on  the 
experience  of  the  cosmetic  firms  and  the  outlook  for  replacing 
animal tests. 

3. 

DG XII 

Since  1985  the  Commission  has  been  supporting  research  in  the  field  of 
new  in  vitro  alternatives  to  animal  experiments  in  pharmaco-toxicology 
applicable to the cosmetic  industry. 

The  BIOTECH  II  programme  launched  after  the  BAP,  BRIDGE  and 
BIOTECH  I programmes  is also  contributing  to the development  of these 
in-vitro alternatives applicable to cosmetic products. Following the second 
call  for  proposals,  three  projects  are  being  funded  with  a  total  budget  of 
ECU 3 825 000. 

The projects are: 
* 

. 

immuno-pharmaco-toxicological  model:  human 

BIO4-CT96-0086: 
New 
reconstructed epidermis containing Langerhans cells 
Coordinator:  Dr. Rainer  Schmidt 

* 

* 

L'OREAL  S.A. 
Centre Charles Zviak 
9a, rue du Général Roguet 
F - 92383 Clichy Cedex 

BIO4-CT96-0036: 
Development 
of 
immortalized cell lines for testing skin irritancy 
Coordinator:  Professor  Charles Lapière 

systems  using 

vitro 

in 

human 

Laboratory of Experimental  Dermatology 
Université de Liège 
Tour de Pathologie, B 23 
B - 4000 Liège 

BIO4-C96-0246: 
Development  for  in vitro tests  for  drug  allergenicity  and  B 
cell switching to IgE synthesis 
Coordinator:  Dr. I. W. Coleman 
of 

Pharmacology 

& 

Department 
Therapeutics 
New Medical  Building 
Ashton  Street 
GB - Liverpool L69 3BX 

4. 

COLIPA 

COLIPA/SCAAT  (the  European  Cosmetic,  Toiletry  and  Perfumery 
Association/  Steering Committee on Alternatives to Animal  Testing) 

Following the international two-day  scientific  symposium  organised  at the 
end  of  1995,  Scaat  has  continued  its  efforts  towards  getting  validated 
regulatory 
alternative  methods  accepted  and 
framework. 

introduced 

into 

the 

On  EYE  IRRITATION,  the  results  of  the  COLIPA  validation  study 
became  fully  available  and  were  submitted  for  review to  ECVAM  and  to 
the  SCC  and  DG  XXIV.  The  relevant  working  party  has  drafted  a  first 
paper  on  the  outcome  of  the  study,  which  has  been  accepted  for 

23 

publication  in  Toxicology In  Vitro. Further  statistical  analysis  of the  data 
generated by the study is in progress. 

On  SKIN IRRITATION, the specific  working party  is drafting  guidelines 
on  human  testing  of  cosmetic  ingredients,  expected  to  be  available  early 
1997. This follows  the issuing  of guidelines  on human  testing  of  finished 
products,  issued  in  1995  and  now  published  in  Food  and  Chemical 
Toxicology.  Both  guidelines  incorporate  the  need  for  strict  ethical 
standards for such testing. 

On  PERCUTANEOUS  ABSORPTION,  a  working  party  has  been 
collecting  data  generated  by  the  cosmetic  industry  substantiating  the 
validity  of  in  vitro  testing,  as  laid  down  in  the  COLIPA  guidelines 
prepared  in  1995. An  extensive  data package  has  been  made  available  to 
ECVAM, to OECD, and to the SCC and DG XXIV. 

On  PHOTOIRRITATION,  a second  phase  of  the  EU/COLIPA  validation 
study  has  been  successfully  completed  and  discussed  with  the  SCC.  The 
SCC has asked for a special study to verify  the applicability  of the in vitro 
method  for  UV-filters  listed  in  Annex  VII  of  the  Cosmetics  Directive. 
This special  study will  be sponsored  by ECVAM  and carried  out over the 
next year. 

SCAAT has also created  a working  party  "SKIN SENSITISATION".  The 
main  objective  of  this  new  group  is  to  define  and  execute  a  research 
programme on mechanisms, which could pave the way to suitable  in vitro 
test methods. 

5. 

OECD 

OECD  Guidelines  for  the  Testing  of  Chemicals  and  the  Principles  of 
Good  Laboratory  Practice  (GLP)  are  developed  in the  broader  context  of 
the  concept  of  mutual  acceptance  of  data.  Both  of  these  instruments  for 
ensuring  harmonized  data  generation  and  data quality  are  an  integral  part 
of  the  1981  OECD  Council  Decision  on  the  Mutual  Acceptance  of  Data 
(MAD).  In accordance  with  this  decision,  OECD's  28  Member  Countries 
agree  that  data  generated  in  the  testing  of  chemicals  in  any  OECD 
Member  Country,  when  in  accordance  with  OECD  Test  Guidelines  and 
Principles of GLP, shall be accepted  in any other Member  Country  for  the 
purpose of assessment and other uses relating to the protection of man and 
the  environment.  The  practical  consequence  of  this  decision  is  that  data 
developed  in a Member Country  under these conditions  and  submitted  for 
fulfilling  regulatory requirements  in another Member  Country,  cannot  and 
will  not  be  refused.  Consequently,  OECD  Test  Guidelines  are  globally 
accepted  as  the  standard  methods  for  safety  testing  and  as  such  enhance 
the  validity  and  international  acceptance  of  test  data.  Recognising  the 
significance  of  OECD  Test  Guidelines,  the  European  Commission 
strongly  supports work on the development  of new test guidelines  and the 
updating of existing ones. 

24 

B. 

S T A T I S T I CS  ON  A N I M AL  E X P E R I M E N TS 

On  numerous  occasions  the  Commission  has  urged  the  Member  States,  both 
orally and in writing, to provide the necessary statistics. 

1995: 

1. 

2. 

3. 

4. 

Eight  Member  States  reported  that  finished  cosmetic  products  had  not 
been  tested  on animals  on their  territory  (Italy,  Greece,  Belgium,  Ireland, 
Sweden, Finland, Luxembourg, Germany). 

Six  Member  States reported  that  cosmetic  ingredients  had  not  been  tested 
on  animals  on  their  territory  (Greece,  the  Netherlands,  Ireland.  Sweden, 
Finland, Luxembourg). 

Only  three  Member  States  (Austria,  France,  the  United  Kingdom) 
communicated  figures  on the number  of  animals  used, while  emphasising 
that  these  figures  were not  interprétable  and  that  there  was  uncertainty  as 
to what they really signified.  In these circumstances the  1995 Report could 
not present  comparative tables comprising  numerical  data, because  such a 
table would have given a false picture of reality. 

As regards the declarations  on thé absence of tests, it is worth  mentioning 
that  certain  Member  States  that  do  not  manufacture  ingredients  will 
certainly  be  using  ingredients  tested  in  other  Member  States  or  in  third 
countries and that  certain ingredients  used  in cosmetic products  may  have 
been tested for other purposes. 

Following the final reminder from  the Commission in October  1996: 

- 

- 

- 

- 

Ireland  and Finland  confirmed  that cosmetic products had  not  been  tested 
on  animals  in  their  countries  in  1996.  Sweden  did  likewise  for  1995  but 
reported that in November  1996 it did not have data relating to  1996. 

Portugal  reported  that cosmetic  products  were not tested  on animals  in its 
country. 

Germany  confirmed  that finished  products were not tested  on animals  and 
that it had no data as regards ingredients testing. 

Finally,  in  the  Netherlands  the  Experiments  on  Animals  Act,  which 
entered  into  force  on  5 February  1997, provides  that  animal  experiments 
may  not  be  carried  out  with  a  view  to  developing  new  cosmetics  or  to 
testing  existing  cosmetics  which  come  within 
the 
Commodities Act. 

the  remit  of 

The  Commission  regrets  that  it  does  not  have  more  statistics  and  is  pursuing  its 
efforts  to obtain them. 

25 

C. 

STATE OF PROGRESS IN 1996  IN EACH INDIVIDUAL AREA 

1. 

Photoirritation/phototoxicity 

ECVAM/COLIPA 

The  biométrie  analysis  (=  statistical  evaluation)  of  the  data  produced 
during  the  second  validation  phase  has  been  completed  for  the  3T3 NRU 
PI1 cell viability test. 

The  raw data were  imported  into  an EXCEL  file  and  checked  for  internal 
consistency.  A  new  mathematical  model  was  developed  to  analyse  the 
complex dose-response relationships. 

The  predictive  value  was  evaluated  by  comparing 
in  vivo 
photoirritation  classification  of the  materials  tested  with  the  classification 
based on the values and biological endpoint of the in vitro test. 

the 

The variability  of the in vitro classification  was calculated  on the  basis  of 
the rate of classification  errors. 

The degree of association between the results of the tests conducted by the 
different  laboratories was subjected to statistical analysis. 

The  results  of  the  biométrie  analysis  (dated  29°  March  1996)  indicate 
that  the  NRU  assay  is  capable  of  correctly  predicting  the  irritation 
potential  in  man  in  regard  to  most  of  the  substances  tested.  It  may  be 
noted that: 

a. 

b. 

c. 

(In  many  cases)  the  PIF  does  not  represent  the  exactly  measured 
values  but  estimates  which  are  below  or  above  the  critical  value 
(>5<) established  in phase I of the validation  study. 

The  prediction  model  proposed  in  the  SOP  (Standard  Operation 
Procedure)  of  the  3T3  NRU  test  predicts  well  the  in  vivo 
phototoxicity of most of the substances tested. 

The  variability  of  the  PIF  values  grows  with  the  increase  in 
absolute PIF values. 

The  number  of independent  tests  in each  laboratory  was too  small 
to authorise a valid estimate of intralaboratory  variability  data; 

NRU: Neutral  red  uptake  assay",  which  uses the cells as target  and cell toxicity  as the  outcome. 

26 

d. 

The  effects  of  data  variability  on  the  in  vitro  classification  are 
negligible,  as  the  computer  analysis  of  the  classification  errors 
demonstrates. 

The  technical  problems  responsible  for  the  incorrect  classification  of 
certain test materials have been identified  and will be taken into account in 
evaluating the performance  of the 3T3 NRU PI test in the final report. 

In particular, one should bear in mind: 

possible in vivo classification  errors 
errors in preparing the solution due to the total  lack  of  information 
on the coded test  substances 
the deviations in regard to the SOP. 

- 

- 

SCC 

Following  an  SCC  recommendation,  which  emphasised  the  importance 
of  verifying  the  applicability  of  the  NRU  test  in  evaluating  the  safety  of 
Annex  VII  UV  filters  and  creating  a  database,  a  third  experimental 
phase, directed by ZEBET,  and subsidised and coordinated by ECVAM, is 
planned  for  1996. The objectives  of this study are to test the Annex VII 
UV filters and to prepare an optimised protocol with a view to  submitting 
a  draft  guideline  on  in  vitro  photoirritation  to  the  OECD.  The  first 
results of the third phase should be in by September 1997. 

OECD 

The OECD  group of national  coordinators  has decided  not to develop  the 
in  vivo  method  on  its  schedule  before  termination  of  the  third  in  vitro 
validation  phase  at  end  1997.  If  the  in  vitro  method  has  not  been 
completed by that date, the OECD will try to develop the in vivo method. 

2. 

Percutaneous  absorption 

COLIPA 

In  May  1996  a  method  proposed  in  the  ECVAM  workshop  report,  as 
discussed by the industry, ECVAM and OECD secretary, was presented to 
the OECD. 

This  draft,  which  is  currently  being  studied  by  the  OECD  group  of 
national  coordinators,  explicates  the  general  principles  governing  the 
design  of  protocols  for  skin  penetration  tests  using  the  excised  skin  of 
different  mammalian  species  post  mortem.  The  skin  is  excised  from  the 
dead animals: 

[- 

"know-how" regarding the substance tested and choice of vehicle; 

27 

choice of the type of cell, receptor fluid, cutaneous  membrane  and 
control of membrane integrity; 
potential significance  of the skin metabolism; 
(finite  or infinite) dose and duration of application; 
temperature and humidity conditions; 
sample collection and analysis; 
presentation of the results and content of the final report.] 

- 
- 
- 
- 

To  support this guideline COLIPA  submitted  to the OECD, ECVAM  and 
the  SCC  a  dossier  consisting  of  "in-house"  data  and  articles  from  the 
literature  designed  to  demonstrate  the  predictive  value,  reliability  and 
robustness of the in vitro approach. 

It may be summarised as follows: 

* 

Predictive value 

The  in  vitro  tests  are  useful  predictors  of  in  vivo  cutaneous 
absorption. 

[Bearing  in  mind  the  variability  of  in  vivo  data,  there  is  good 
correlation between 
- 
- 

in vitro (pig) and in vivo (rat) data for  10+8 hair dyes; 
in vitro (rat) and in vivo (rat) data for  8 coded substances of 
different  solubility; 
in vivo (pig) and in vitro (man) data for 7 colouring agents; 
in  vitro  (pig)  and  in  vivo  (man)  data  for  1  UV  filter  in 
ethanol solution. 

- 
- 

The skin of the pig's ear is a very good model of the human skin in in vitro 
cutaneous absorption tests of oestradiol.] 

It is possible to design prediction models  of skin pharmacokinetics  on the 
basis of in vitro tests. 

[The  in  vitro  data  in  the  rat  can  be  used  in  combination  with  a  skin 
pharmacokinetic mode. 

The  model  correctly  predicts  experimental  in  vivo  measurements  in  man 
for an ester in suspension in a mixture of organic solvents and  surfactants.] 

* 

Reliability 

"In-house"  experience  in  this  domain  pertained 
to  different 
categories of cosmetic  ingredients,  including  UV filters, hair  dyes, 
surfactants, mineral hydrocarbons, etc. 

* 

Robustness 

28, 

The  dossier  contains  scanty 
intra-  and 
interlaboratory  variability  of  the  results  and  their  statistical 
analysis. 

information  on  the 

(Kp)  and 

their  standard 
[The  skin  penetration  coefficients 
deviations  give  an  idea  of  the  degree  of  reproducibility  of  the 
results  obtained  in  a  series  of  in  vitro  tests  conducted  on  benzyl 
alcohol.  Good  interlaboratory  reproducibility  is  observed  in  one 
study  conducted  in  two  laboratories  using  the  same  in  vitro 
protocol (rat) to measure the skin penetration of two UV filters.] 

* 

Influence  of operating conditions 

There  are  some  articles  in  the  literature  that  provide  patchy  and 
unsystematic  information  on  the  influence  of  storage  conditions, 
the type of cell used, and the batches of skin used. 

The use of the excised skin of fresh  or deep-frozen  pig does 
not influence  the results  for two UV filters (lipophiles)  and 
lactic acid (a hydrophile); 
the  type  of  cell  used  (static  or  continuous  flux)  does  not 
the  cutaneous  absorption  of  water-soluble 
influence 
substances through various types of membranes taken  from 
different  species  (pig,  rat,  man)  into  different  destination 
solutions; 
the  choice  of  the  destination  solution 
substances which have low solubility in water; 
batches  of skin taken  from  three different  animals  (rats)  do 
the  data  on  cutaneous  absorption  and 
not 
distribution  through  the  skin  in  respect  of  two  UV  filters 
tested using the same vehicle.] 

is  crucial  for 

influence 

[- 

- 

- 

- 

OECD 

The  USA  and  the  EU  are  at  odds  about  the  in  vitro  approach  within  the 
OECD's group of national coordinators. 

At its 7th meeting, held in Paris on  18 and  19 September  1996, the group 
of national coordinators  decided: 
1. 

to  devote  a  forthcoming  workshop  to  the  study  of  existing  in 
vitro percutaneous absorption data; 
to  base  the  decisions  on  a  guideline  document  to  be  prepared  in 
the  coming  year  by  the  OECD  Secretariat  on  the  criteria  for  the 
validation  and  acceptance  of  alternative  methods  (on  the  basis 
of the Solna workshop report); 
to  develop  a  dual  guideline  on  in  vivo  and  in  vitro  tests,  in  the 
event of rapid development of the in vitro dossier. 

2. 

3. 

SCC 

29 

Although  the  SCC  has  emphasised  that  the  test  protocols  used  by 
industry  were  not subjected  to a formal  validation  test and  although  it 
recommended  that  the  existing  documentation  be  supplemented,  notably 
as  regards  intra-  and  intra-laboratory  reproducibility  and  the  influence  of 
the  vehicle  on  the  release  of  the  cosmetic  ingredients,  the  SCC  is 
convinced  of  the  relevance  of  the  in  vitro  methods  and  has  in  recent 
years  agreed  to  draw  on  in  vitro  percutaneous  absorption  data  in  the 
evaluation of the safety  of several cosmetic ingredients for human use. 

3. 

Eye irritation 

ECVAM/COLIPA 

The  international  EC/HO  validation  study  of  alternatives  to  the 
Draize  eye irritancy  test did not achieve  the expected  objectives  but it 
inspired  the  organisation  of  an  ECVAM/ERGATT  workshop  on  the 
practical  aspects  of validation  and  the  preparation  of  a  prevalidation 
schedule by ECVAM, as well as the planning of the COLIPA  study. 

Limited  results  were  obtained  for  a  small  number  of  protocols  in 
COLIPA's  first  international  validation  phase  of  alternatives  to  the 
Draize test, where prediction models had been prepared for each test. 

Statistical  evaluation  of  the  results  of  the  first  validation  phase  indicate 
that the most promising  protocols  are FLtest2, TEA3  and RBCtest,4  which 
conform  reasonably  with  their  prediction  models;  however,  for  the  first 
two  more  reproducibility  data  is required  because  in  each  case  they  have 
only  been  used  by  two  large  laboratories,  while  the  utility  of  the  FL  and 
their 
RBC 
classification  models  is  not  universally  supported.  Moreover,  no  attempt 
has  been  made  to  evaluate  the  idea  of  a  battery  of  two  or  more  tests  to 
replace in vivo assays. 

tests  has  been  challenged  because 

the  pertinence  of 

Currently  there  are  no  validated  alternative  methods  capable  of 
replacing the OECD-405 in vivo eye irritancy test. 

4. 

Skin irritation 

ECVAM 

Fluorescein  leakage test, measures the damage caused to a cell barrier. 

Tissue  Equivalent  Assay,  measures  the time  required  to cause  a 50% reduction  in the  viability  of 
cells in reconstituted  human skill. 

Red blood cell haemalysis test, used to evaluate damage to the cell membranes. 

50. 

Following  a prevalidation  exercise  in  1995  on  skin  corrosion  tests  (TER, 
CORROSITEX  and  SKIN and EPISKIN), ECVAM  undertook  a  formal 
validation  study  involving four  skin corrosion tests and  60 test materials, 
whose results are expected in 1997. 

Considerable  progress has  been  made  in  developing  a database  to  predict 
irritation  potential.  However  the  in  vitro  tests  currently  being  validated 
concern  highly  irritant  substances  and  so  this  research  -  which  is  very 
useful  for  classifying  and  labelling  dangerous  substances  -  is  only  of 
limited use in evaluating the skin tolerance of cosmetic ingredients, which 
are  a  priori  weakly-  or  non-irritant  substances  (at  their  concentration  of 
use). 

There  are  to  date  no  validated  alternative  methodologies  capable  of 
replacing  the  OECD  404  in  vivo  skin  irritancy  test.  An  ECVAM 
workshop  on  human  skin  equivalents  and  their  uses  is  planned  for 
1997. 

OECD 

A  draft  test  strategy  for  determining  the  skin  irritation  potential  of 
chemical  substances  is  on  the  programme  of  the  OECD  group  of 
national coordinators. 

The strategy proposed  by the  OECD  envisages  first  eliminating  the  most 
irritant substances  through examination  of the structure  activity  relations 
and structure property  relations,  as  well as  by using  information  derived 
from  in vitro corrosion tests, before considering recourse  to  conventional 
tests on rabbits, in vivo, or the use of human volunteers. 

5. 

Skin  sensitisation 

Identifying  skin  irritation  potential  which  manifests  itself  as  contact 
allergy is important in evaluating the safety  of cosmetic ingredients. 

The  impressive  research  work  done  up  to  now  has  helped  clarify  our 
understanding  of the mechanistic bases of skin sensitisation.  It seems  that 
predicting 
feasible  only  by  combining 
information  derived from  several supplementary tests. 

sensitisation  potential 

is 

ECVAM 

The  report  of  ECVAM  workshop  19  reviews  the  situation  and  contains 
recommendations  for  research  aimed  at  replacing  current  animal  tests, 
viz.: 

* 

refine  the  DEREK  expert  system  identifying  the 
structural  alerts  of  skin  sensitisation  and  develop 
supplementary 
the  SARs 
(Structure Activity  Relationships) 

systems  based  on 

31 

* 

* 

* 
* 

standardise  the  tests  "on  cultures"  of  the  most 
promising  in  vitro  cells,  and  notably  study  the 
essential  role  of  mediators  derived  from  human 
dendritic  cells  and  standardise  the  methods  of 
isolating and cultivating these cells 
develop  other  in  vitro  models,  notably  on  skin 
expiants 
develop an in vitro skin metabolism  system 
develop  an  adequate  database  on  the  basis  of  these 
tests, through  a validation  exercise  using  a  suitable 
in vivo database. 

ECVAM  hopes  to  support  a  prevalidation  study  on  an  in  vitro  test,  in 
1997. 

Bearing  in mind  the complexity  of the process and the fact  that  predicting 
sensitising  potential  is  a  difficult  task  because  of  the  variability  of 
individual  response,  definitive  results  in  this  domain  can  be  expected 
only in the medium term, if not indeed the long term. 

6. 

Skin compatibility  of the finished  product 

The guidelines prepared by COLIPA  in November  1995 on evaluating  the 
skin  compatibility  oi finished  cosmetic  products  in  the  framework  of 
strictly  controlled  clinical  studies,  which  were  informed  by  ethical 
considerations  and  based  on  prior  knowledge  of  the  composition  and 
stability  of  the  tested  products  and  prior  evaluation  of  the  toxicity  data 
pertaining  to  the  ingredients  used  in  the  product,  have  been  published  in 
Food and Chemical Toxicology [34 (1996) 651-660]. 

ISSN 0254-1475 

COM(97)  182  final 

DOCUMENTS 

EN 

10  15  02 

Catalogue  number  :  CB-CO-97-176-EN-C 

ISBN  92-78-19036-5 

Office  for  Official  Publications of the European  Communities 

L-2985  Luxembourg 

S3